Efficacy and safety of fenfluramine in the treatment of Dravet syndrome - literature review

Dravet Syndrome is a severe, drug-resistant, and rare epileptiform disorder that is typically presented in the first year of life in an otherwise healthy child. It is characterized by prolonged seizures that are often resistant to current anti-epileptic drug regimens, which made them poorly controlled, and almost 50% of patients experience at least four tonic-clonic seizures per month. There are three new medicines: stiripentol, cannabidiol, and fenfluramine, with documented efficacy and safety as adjunctive therapies in pharmacoresistant Dravet syndrome treatment. This study aimed to assess the efficacy and safety of fenfluramine in the treatment of Dravet syndrome. Our study material consisted of publications, which were found in PubMed, Google Scholar, and Embase databases. In order to find the proper publications, the search has been conducted with the use of a combination of keywords like: “fenfluramine”, “Dravet syndrome”, “epilepsy treatment”, “Dravet syndrome pediatric patients”. The first step was to find proper publications from the last 10 years. The second step was to carry out an overview of the found publications. Results of mentioned studies proved that in Dravet syndrome, fenfluramine provided a significantly greater reduction in convulsive seizure frequency compared with placebo. No patient developed valvular heart disease or pulmonary arterial hypertension, the side effects that occurred during its use were mild and the drug was generally well-tolerated. The bioequivalence and tolerability of single oral doses of fenfluramine hydrochloride oral solution in the fed and fasted states support drug administration without regard to meals. Fenfluramine may represent a new important treatment option for Dravet syndrome.

PROVE—Phase IV Study of Perampanel in Real-World Clinical Care of Patients with Epilepsy: Interim Analysis in Pediatric Patients

PROVE is a retrospective, phase IV study assessing retention, dosing, efficacy, and safety of perampanel when administered to patients during routine clinical care. We report an interim analysis of preadolescent (1 to <12 years) and adolescent (12 to <18 years) patients. Data were obtained from medical records of patients with epilepsy initiating perampanel after January 1, 2014; cut-off date for this analysis was October 10, 2018. Overall, 151 preadolescent and 183 adolescent patients were included. Retention rates following 24 months on perampanel were 42.5% (preadolescent subgroup; n = 31/73) and 55.7% (adolescent subgroup; n = 54/97). Treatment-emergent adverse events occurred in 53 (35.1%) preadolescent (most common: aggression, irritability, and somnolence) and 78 (42.6%) adolescent patients (most common: somnolence, aggression, and dizziness). These data indicate that daily oral doses of perampanel are generally well tolerated during routine clinical care, with favorable retention rates for ≤2 years, in patients aged 1 to <18 years.

Impact of a Novel Anticoccidial Analogue on Systemic Staphylococcus aureus Infection in a Bioluminescent Mouse Model

In this study, we investigated the potential of an analogue of robenidine (NCL179) to expand its chemical diversity for the treatment of multidrug-resistant (MDR) bacterial infections. We show that NCL179 exhibits potent bactericidal activity, returning minimum inhibitory concentration/minimum bactericidal concentrations (MICs/MBCs) of 1–2 µg/mL against methicillin-resistant Staphylococcus aureus, MICs/MBCs of 1–2 µg/mL against methicillin-resistant S. pseudintermedius and MICs/MBCs of 2–4 µg/mL against vancomycin-resistant enterococci. NCL179 showed synergistic activity against clinical isolates and reference strains of Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa in the presence of sub-inhibitory concentrations of colistin, whereas NCL179 alone had no activity. Mice given oral NCL179 at 10 mg/kg and 50 mg/kg (4 × doses, 4 h apart) showed no adverse clinical effects and no observable histological effects in any of the organs examined. In a bioluminescent S. aureus sepsis challenge model, mice that received four oral doses of NCL179 at 50 mg/kg at 4 h intervals exhibited significantly reduced bacterial loads, longer survival times and higher overall survival rates than the vehicle-only treated mice. These results support NCL179 as a valid candidate for further development to treat MDR bacterial infections as a stand-alone antibiotic or in combination with existing antibiotic classes.

Long-term high-dose l-arginine supplementation in patients with vasculogenic erectile dysfunction: a multicentre, double-blind, randomized, placebo-controlled clinical trial

Purpose The current randomized, double-blind, placebo-controlled clinical trial addressed the effects on penile erectile function of relatively high daily oral doses (6 g/day) of l-ARG for 3 months (N = 51) compared to placebo (N = 47), in patients with vasculogenic ED, with comparison between mild–moderate and severe vasculogenic ED. Methods The outcome measures included IIEF-6 score and cavernous arteries peak systolic flow velocity (PSV) at dynamic penile duplex ultrasonography (PDU). Results l-ARG supplementation for 3 months significantly increased IIEF-6 score in the overall cohort (p < 0.0001) and in subgroups of patients with mild–moderate (p < 0.0001) and severe (p = 0.007) vasculogenic ED; PSV was significantly increased in the overall cohort (p < 0.0001) and in patients with mild–moderate (p < 0.0001), but not severe vasculogenic ED. At study completion, 74% of patients improved ED degree category, although only 24% of patients, mainly belonging to the baseline category of mild ED, reached IIEF-6 scores compatible with absence of ED; moreover, 20% of patients, exclusively belonging to the baseline category of mild–moderate vasculogenic ED, reached PSV values compatible with absence of ED. Conclusion The results of the current study demonstrated that supplementation with relatively high doses of l-ARG as a single compound for 3 months significantly improved penile erectile function, assessed by both IIEF-6 score and PSV at dynamic PDU in patients with mild–moderate, and improved IIEF-6 score, but not PSV, in patients with severe vasculogenic ED, therefore suggesting that l-ARG might be an alternative treatment in mild–moderate vasculogenic ED patients experiencing adverse effects or with contraindications for chronic treatment with PDE5i compounds.

Evaluation of acute and subchronic toxicity of “Tran Chau Nguu Hoang Hoan” in experimental animals

“Tran chau nguu hoang hoan” was prepared from 12 herbal ingredients. So far, the safety of this product, has not been reported yet. Thus, this study aimed to evaluate the acute and subchronic toxicity of “Tran chau nguu hoang hoan” through oral administration in experimental animals. The acute toxicity was determined by the method of Litchfield Wilcoxon in mice at the doses of 2.42 g/kg b.w/day to 6.04 g/kg b.w/day. The subchronic toxicity was evaluated followed the Guideline of WHO and OECD in rats with oral doses of 58.0 mg/kg b.w/day and 174.0 mg/kg b.w/day for 12 consecutive weeks. As a result, in the course of the acute toxicity test, the mice showed no abnormal sign or death. In terms of the subchonic toxicity test, hematological indexes, hepato-renal functions and microscopic images of liver and kidney were unchanged. In conclusion, “Tran chau nguu hoang hoan” does not appear to produce acute and subchronic toxicities in mice and rats.

The study of acute and subchronic toxicities of Da Dai Trang HVD capsules in experimental animals

The purpose of this research is to evaluate the acute and subchronic toxicities of DA DAI TRANG HVD capsules through oral administration in experimental animals. The acute toxicity was determined by the method of Litchfield Wilcoxon in Swiss mice. The subchronic toxicity was evaluated by the recommendation of WHO and OECD in Wistar rats with oral doses of 1.44 g/kg/day (equal to recommended human dose) and 4.32 g/kg/day (3 times as high as recommended human dose) in 4 consecutive weeks. As a result, DA DAI TRANG HVD capsules at the highest dose used for mice (99.9 g materials/kg) did not express acute toxicity in mice. In term of the subchonic toxicity test, DA DAI TRANG HVD had no deleterious effect on hematological parameters, hepato-renal functions, macroscopic and microscopic images of livers and kidneys of rats. In conclusion, DA DAI TRANG HVD capsules did not produce the acute and subchronic toxicities in Swiss mice and Wistar rats.

Subchronic oral toxicity of Rabella powder in experimental rats

It has recently become obvious that the prevalence of obesity has been rapidly increasing in Vietnam, as well as other countries, over the past two decades. There has been a current trend for researchers to discover new natural ingredients which are safe and effective in the treatment of obesity. RABELLA powder was a herbal-derived product which contained Amorphophalus konjac (K. Koch starch). This plant was used as an oral medication for controlling body weight in the past as well as in the present. So far, the safety of this product, has not been reported yet in Vietnam. Thus, this study was designed to assess the subchronic toxicity of RABELLA powder in Wistar rats. The method used in this study followed the guidance of the World Health Organization and Organization for Economic Co-operation and Development; 2 oral doses of 1.2 g/kg b.w/day and 3.6 g/kg b.w/day was administered to rats for 12 consecutive weeks. The results show that RABELLA powder caused no significant change in the general condition, hematological indexes, functions and microscopic images of livers and kidneys. We conclude that RABELLA powder did not cause subchronic toxicity in experimental rats. Moreover, this also revealed partly the safety of RABELLA powder in clinical practice.

Effects of Drugs Reabsorption Time Delays for a Pharmacokinetics Model in Humans

A three-compartmental delay model is formulated to describe the pharmacokinetics of drugs subjected to both intravenous and oral doses with reabsorptions by the central compartment. Model dynamics are analyzed rigorously, and two equilibrium points are obtained to be locally asymptotically stable under certain conditions. Time delays used as lags in reabsorption of drugs by central compartment from other two compartments caused rebounds or peaks and fluctuations in the time profiles for amounts of drug in all the compartments. Sensitivity analysis revealed that elimination rates decrease the amounts in all compartments. Furthermore, reabsorption rates cause superimposition at the initial phases of the drug amount profiles; subsequently, the quantities decrease in compartment one and increase in compartments two and three, respectively.

Our Exciting Journey to ACT-451840

We describe our work resulting in the selection of ACT-451840 ( 38 ) as a novel antimalarial drug with a novel mode of action. The compound was broadly characterized in vitro as well as in vivo in rat PK experiments as well as two different mouse malaria models. In the P. berghei infected mouse model cure could be achieved at oral doses of 300 mg/kg over 3 consecutive days. ACT-451840 was clinically investigated up to an experimental human malaria infection model, where therapeutic effects could be shown.